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HIV latency and integration site placement in five cell-based models

  • Author(s): Sherrill-Mix, Scott
  • Lewinski, Mary K
  • Famiglietti, Marylinda
  • Bosque, Alberto
  • Malani, Nirav
  • Ocwieja, Karen E
  • Berry, Charles C
  • Looney, David
  • Shan, Liang
  • Agosto, Luis M
  • Pace, Matthew J
  • Siliciano, Robert F
  • O’Doherty, Una
  • Guatelli, John
  • Planelles, Vicente
  • Bushman, Frederic D
  • et al.
Abstract

Abstract Background HIV infection can be treated effectively with antiretroviral agents, but the persistence of a latent reservoir of integrated proviruses prevents eradication of HIV from infected individuals. The chromosomal environment of integrated proviruses has been proposed to influence HIV latency, but the determinants of transcriptional repression have not been fully clarified, and it is unclear whether the same molecular mechanisms drive latency in different cell culture models. Results Here we compare data from five different in vitro models of latency based on primary human T cells or a T cell line. Cells were infected in vitro and separated into fractions containing proviruses that were either expressed or silent/inducible, and integration site populations sequenced from each. We compared the locations of 6,252 expressed proviruses to those of 6,184 silent/inducible proviruses with respect to 140 forms of genomic annotation, many analyzed over chromosomal intervals of multiple lengths. A regularized logistic regression model linking proviral expression status to genomic features revealed no predictors of latency that performed better than chance, though several genomic features were significantly associated with proviral expression in individual models. Proviruses in the same chromosomal region did tend to share the same expressed or silent/inducible status if they were from the same cell culture model, but not if they were from different models. Conclusions The silent/inducible phenotype appears to be associated with chromosomal position, but the molecular basis is not fully clarified and may differ among in vitro models of latency.

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